Benzodiazepine dependence can limit the clinical use of this important class of drugs and contribute to their abuse. Emerging evidence suggests that the chronic effects of neuroactive steroids are different from those of benzodiazepines; such differences can be exploited to improve our understanding of GABAA receptor function, particularly during chronic treatment, and might offer clinical advantages. Like benzodiazepines, neuroactive steroids are positive GABAA modulators, and when administered acutely, they produce effects that are qualitatively similar to those of benzodiazepines. However, studies supported by this grant have demonstrated fundamental differences between neuroactive steroids and benzodiazepines during chronic treatment. In rats receiving the benzodiazepine flunitrazepam chronically, sensitivity to flunitrazepam decreases (i.e., tolerance develops), whereas when rats receive the neuroactive steroid pregnanolone chronically, sensitivity to flunitrazepam increases. Although this exciting observation could be exceptionally beneficial clinically, the generality of this finding has not been investigated. Moreover, the extent to which these unexpected changes in sensitivity predict the potency of these drugs to reverse withdrawal is not known. Aim 1 will examine potency changes during chronic treatment to understand the range of conditions under which these differences occur. The ability of neuroactive steroids to modulate benzodiazepine tolerance, dependence and withdrawal will be evaluated in Aim 2 to determine whether treatment with neuroactive steroids, either instead of or in addition to, benzodiazepine treatment reduces tolerance and prevents the emergence of withdrawal. Together, these two specific aims will explore changes in GABAA receptor function that occur during chronic treatment and determine whether neuroactive steroids could provide unique strategies for preventing or reversing benzodiazepine withdrawal. Because such strategies might be equally useful in treating ethanol withdrawal, the final specific aim will compare ethanol to neuroactive steroids. Aim 3 will build upon another key finding of these studies which indicates that the discriminative stimulus effects of neuroactive steroids are not identical to those of ethanol, despite their overlapping mechanisms of action; this Aim will examine differences between ethanol and neuroactive steroids under a broader range of conditions. PUBLIC HEALTH RELEVANCE: Benzodiazepine dependence limits the clinical use of these drugs. This grant evaluates differences in the chronic effects of benzodiazepines and neuroactive steroids and investigates the possibility of using neuroactive steroids to reduce the development or expression of benzodiazepine tolerance and dependence.